Based on our work as well as that of others, we have formulated a working hypothesis that the behavioral augmentation induced by chronic amphetamine intoxication is the result of specific permanent alterations in the nigrostriatal and mesolimbic dopamine (DA) systems. The goal of the studies described in this application is to understand the neurochemical basis of these chronic amphetamine effects (CAE). Our general research plan can be divided into three sections on the basis of the techniques employed. Behavioral studies will be used to characterize certain aspects of the relevant chemical and anatomical loci underlying the CAE. In particular, we will compare the behavioral effects of challenging doses of d-amphetamine with the effects of non-amphetamine stimulants like cocaine, methylphenidate and apomorphine. We will also examine the role of the endorphin systems in the development of the CAE. Neurochemical studies will concentrate to determining the role of DA receptor binding, DA-sensitive adenyl cyclase activity and drug-induced and Ca ions dependent DA release in the CAE. Membrane structural-functional studies will be used to assess how changes in synaptic and vesicle membrane structure and composition are related to the development and maintenance (in withdrawn animals) of the CAE. Using microinjection techniques to label specifically limbic or striatal DA terminals, we propose to follow changes in the synthesis, transport and turnover of the lipid components of synaptic and vesicle membranes both during chronic amphetamine intoxication and during drug withdrawal. In addition, we propose to use procedures for the selective solubilization and cross-linking of membrane components to determine if CAE are associated with any gross changes in DA synaptic membrane architecture. Finally, we propose to study how the systematic manipulation of synaptic membrane lipids in normal and CAE animals can effect DA functions. Overall, the results obtained from the proposed studies should provide significant new insights into the relationships among membrane structure and function and normal abnormal behavior.